1. Field of the Invention
The present invention relates to a method for checking the permeability rate of a closed container with respect to a medium, in particular for checking the permeability rate of a film-type container for accommodating a pharmaceutical active constituent formulation.
2. Description of the Related Art
The containers serve inter alia to protect pharmaceutical active constituent formulations against outside environmental influences which, depending on the circumstances, may affect the pharmaceutical quality of the active constituent formulation, wherein in particular moisture penetrating the containers can adversely affect the active constituent formulation. In addition it is necessary in the case of the containers to prevent the permeability of volatile substances of the active constituent formulations during their storage, in order thereby to counteract any change in the pharmaceutical active constituent formulation.
The containers are in particular primary packagings for pharmaceutical active constituent formulations, such as glass, metal, plastics containers and the like. For packaging tablets, capsules, powders and the like, containers designed as film-type containers, so-called blisters, are used, which as a rule consist of a cover film and a carrier film, one or more cups or wells for receiving the active constituent formulation, tablets or capsules being formed in the carrier film. The cover film and the carrier film may be composed of one or more layers of different or identical materials. The cover film is hermetically connected to the carrier film, e.g. by bonding, welding or sealing. Mechanically intact blisters protect an active constituent formulation embedded therein against the entry or influx of substances. Thus, depending on the material, moisture for example can pass through the upper side of the blister, the lower side or through the edges, into the interior.
Liquid active constituent formulations may be packaged in the aforementioned containers as well as in cartridges, which are used for example as active constituent reservoirs for pharmaceutical liquids in inhalers. Such cartridges are known for example from EP 0 532 873, WO 96/06011, WO 97/39831, WO 00/23037, WO 00/27543, WO 00/049988, WO 01/76849, WO 99/43571 or WO 98/46522. A cartridge may for example be used in an inhaler described in WO 97/12687 or WO 91/14468, with which liquid inhalation formulations may be administered by means of specific water-based or alcohol-based formulations free of propellant gas.
In order to be able to determine the hermeticity of the containers, whether as regards liquids or gases penetrating from the outside, e.g. moisture in the form of water or water vapour, or liquids or gases exiting from the inside, various methods are known from the prior art. This applies in particular to blisters. For example, a container filled with a desiccant is exposed to specific environmental conditions (e.g. 40° C., 75% atmospheric humidity) and is then checked as regards hermeticity via the weight increase of the container over time. Such a method often takes months in order to detect low leakage rates. In a further method a container is sealed, e.g. under a helium atmosphere, helium thereby being trapped in the container. The container is then tested for outflowing helium. In this connection the container may be placed in a measurement chamber, gas exiting from the container being detected with suitable measurement systems connected to the measurement chamber. In this method it is necessary to establish a constantly uniform high helium concentration in the container in order to obtain reproducible results, which is not always easy to realise in a production process. In a further method the container prepared under normal conditions is enclosed in a pressure-stable test chamber that is filled with gas. Carbon dioxide, helium or krypton is normally used as gas. After a certain time the container being investigated is removed from the test chamber and tested for exiting gas. Alternatively the container can be placed in a measurement chamber, following which gas exiting from the container can be detected with suitable measurement systems in the measurement chamber. The applicability of these methods is restricted by the detection limit of the gas in the measurement chamber, since in the case of a per se fluid-type container, in both methods only relatively little gas (ppm range) can penetrate the container and accordingly only very little gas can pass from the container into the measurement chamber.
From WO 2004/034 009 a method is known for testing the hermeticity of closed containers that contain a pharmaceutical active constituent formulation in a chamber provided for this purpose in their interior. A sealed film-type container is charged with a first gas, which differs from a second gas enclosed in the container in that the increase of the first gas in the interior of the container can be analysed. After opening the container and removing part of the gas that is contained in the interior of the chamber for the active constituent formulation, a qualitative and/or quantitative analysis of the removed gas is carried out.